Cyclic nucleotides such as cyclic adenosine-3′,5′-monophosphate (c-AMP) and cyclic guanosine 3′,5′-monophosphate (c-GMP) are concerned with intracellular signal transduction molecules as second messengers. These cyclic nucleotides are degraded by a group of hydrolases generally called phosphodiesterase PDE isozyme) into inactive 5′-AMP and 5′-GMP, respectively.
Up to date, the presence of 11 families of PDE1 to PDE11 has been confirmed (see Current Opinion in Cell Biology, 12, 174-179 (2000)). PDE isozymes have differences in specificity and affinity to substrates, i.e. c-AMP and c-GMP, cell distribution and tissue distribution, etc., and each isozyme has different function in vivo.
Among these PDEs, PDE7 is a phosphodiesterase which has specific affinity to cAMP, and it is reported that it is not inhibited by rolipram, which is a PDE4 inhibitor specific to PDE4 (see J. Biol. Chem., 268, 12925 (1993)). PDE7 is important in activation of T-cells and it is implied that it is useful for the prevention and treatment of T cell-dependent diseases (see Science, 283, 848 (1999)). Also, PDE7 is expressed in airway epitheliocytes, and so it is also implied that it is probable that PDE7 is effective for the diseases in airway (see Am. J Respir. Cell Mol. Biol., 20, 292 (1999)).
Therefore, a drug which inhibits PDE7 is thought to be useful for the prevention and/or treatment of various diseases, i.e. autoimmune diseases (ulcerative colitis, Crohn's diesaes, rheumatism, psoriasis, multiple sclerosis, collagenosis, etc.), inflammatory diseases (obstructive pulmonary diseases, sepsis, pancreatitis, sarcoidosis, nephritis, hepatitis, enteritis, etc.), allergic diseases (asthma, allergic rhinitis, allergic conjunctivitis, seasonal conjunctivitis, atopic dermatitis, etc.), rejection of an organ transplant, graft versus host diseases (GVHD), diabetic diseases, osteoporosis, bone fracture, restenosis, arteriosclerosis, obesity, ischemic reperfusion injury, depression, Parkinson's diseases, dementia, leukemia, etc.
Isoquinoline derivatives are known as follows: for example, in JP63-280069(A), it is disclosed that a compound of formula (A)
(wherein AA is benzo or thieno and R2A and R3A are independently hydrogen or (C1-5)alkyl, or taken together with the carbon atom to which they are attached to form 5 or 6 membered carbocycle and R11A is (C1-4)alkyl, halogen, hydroxy and mA is 0, 1, 2 or 3 when AA is benzo, DA is IbA, etc.:
R1A is hydrogen, (C1-10)alkyl etc, R5′A is hydrogen or (C1-4)alkyl, R4A is (C1-4)alkoxy or —NR9AR10A (wherein R9A and R10A are independently hydrogen, C1-12 branched or unbranched alkyl, alkenyl or alkynyl, etc., or R9A and R10A are taken together with the carbon atom to which they are attached to form pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, etc.)) has heart-protecting activity (groups are extracted for description).
Khim. Geterotsikl. Soedin., 946-949, 7, (1994) discloses a compound of 2-(3,3-dimethyl-3,4-dihydro-(2H)-isoquinoline-1-ylidene)-1-phenylmethan-1-one (Reg No. 163769-77-5).
The specification of WO 02/010135 discloses that a compound of formula (B)
(wherein the explanation of groups are as described in the specification of WO02/010135.) has a cannabinoid (CB) 2 receptor agonizing activity, but no description is found on PDE7 inhibitory activity therein.